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Volume 271, Number 25, Issue of June 21, 1996 pp. 14849-14855
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Tissue-specific Activity of the gamma c Chain Gene Promoter Depends upon an Ets Binding Site and Is Regulated by GA-binding Protein

(Received for publication, November 16, 1995, and in revised form, February 14, 1996)

Sophie Markiewicz Dagger , Rémy Bosselut , Françoise Le Deist Dagger , Jean-Pierre de Villartay Dagger , Claire Hivroz Dagger , Jacques Ghysdael , Alain Fischer Dagger and Geneviève de Saint Basile Dagger

From Dagger  INSERM U429, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15 and  CNRS UMR 146, Institut Curie, Section de Recherche, Centre Universitaire, Bâtiment 110, 91405 Orsay Cedex, France

The gamma c chain is a subunit of multiple cytokine receptors (interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15), the expression of which is restricted to hematopoietic lineages. A defect in gamma c leads to the X-linked severe combined immunodeficiency characterized by a block in T cell differentiation. In order to better characterize the human gamma c promoter and define the minimal tissue-specific promoter region, progressive 5'-deletion constructs of a segment extending 1053 base pairs upstream of the major transcription start site were generated and tested for promoter activity in various hematopoietic and nonhematopoietic cell types. The -1053/+34 construct allowed promoter activity only in cells of hematopoietic origin, and tissue specificity was conserved in all other constructs tested. The region downstream of -90 appeared critical for basal promoter activity. It contains two potential Ets binding sites conserved in the murine gamma c promoter gene, one of which was found essential for functional promoter activity as determined by mutational analysis. The functional Ets binding site was found to bind Ets family proteins, principally GA-binding protein and Elf-1 and could be transactivated by GABPalpha and -beta synergistically. These results indicate that, as already reported for the IL2Rbeta promoter, GA-binding protein is an essential component of gamma c basal promoter activity. Although GABP expression is not restricted to the hematopoietic lineage, its interaction with other specific factors may contribute to the tissue-specific expression of the gamma c gene.


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